This invention relates to 2,3(1H,4H)-quinoxalinedione derivatives which are selective antagonists of N-methyl-D-aspartate receptors. More particularly, this invention relates to 5-heteroaryl-2,3(1H,4H)-quinoxalinedione derivatives and to the preparation of, compositions containing, the uses of and the intermediates used in the synthesis of, such derivatives.
L-Glutamic acid is an excitatory amino acid neurotransmitter whose physiological role in the brain involves interaction with four receptors, three of which are named after the selective agonists NMDA (N-methyl-D-aspartate), AMPA (2-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) and kainate. The fourth receptor is termed the metabotropic receptor. In addition to a binding site for glutamic acid, the NMDA receptor possesses high affinity binding sites for dissociative anaesthetics (e.g. ketamine), polyamines (e.g. spermine), glycine and certain metal ions (e.g. Mg2+,Zn2+). Since the NMDA receptor has an absolute requirement to bind glycine for activation to occur, glycine antagonists can act as functional NMDA antagonists.
In the region of a cerebral infarct, anoxia, for example, causes abnormally high concentrations of glutamic acid to be released. This leads to an over-stimulation of NMDA receptors resulting in the degeneration and death of neurones. Thus, NMDA receptor antagonists, which have been shown to block the neurotoxic effects of glutamic acid in vitro and in vivo, may be useful in the treatment and/or prevention of any pathological condition in which NMDA receptor activation is thought to be important. Examples of such conditions include acute neurodegenerative disorders arising from events such as stroke, transient ischaemic attack, peri-operative ischaemia, global ischaemia (following cardiac arrest) and traumatic head injury to the brain or spinal cord. In addition, NMDA antagonists may be of use in treating certain chronic neurological disorders such as senile dementia, Parkinson""s disease and Alzheimer""s disease. They may also have utility in conditions in which peripheral nerve function has been impaired such as retinal and macular degeneration.
Furthermore, NMDA antagonists have been shown to possess anti-convulsant and anxiolytic activity and may therefore be used to treat epilepsy and anxiety. NMDA antagonists may also attenuate the effects of alcohol withdrawal from physically dependent animals (K.A. Grant et al., J Pharm.Exp.Ther., 260, 1017 (1992)) and thus NMDA antagonists may be of use in the treatment of alcohol addiction and pain. NMDA antagonists may also be useful in the treatment of hearing disorders (e.g. tinnitus), migraine and psychiatric disorders.
EP-A-0572852 describes pyrrol-1-yl-substituted 2,3(1H,4H)-quinoxalinedione derivatives useful for the treatment of neurodegenerative illnesses and neurotoxic disorders of the central nervous system.
EP-A-0556393 disclosed, inter alia, imidazolyl- or triazolyl-substituted 2,3(1H,4H)-quinoxalinedione derivatives with glutamate receptor antagonising activity, particularly NMDA-glycine receptor and AMPA receptor antagonising activities. However, no 5-triazolyl-substituted compounds are specifically described therein.
The present compounds are potent antagonists of the NMDA (glycine site) receptor. In addition, they are highly selective antagonists for the NMDA (glycine site) receptor in comparison to the AMPA receptor to which they have little, if any, affinity.
The present invention relates to a compound of the formula: 
or a pharmaceutically acceptable salt thereof, wherein
R is a 5-membered ring heteroaryl group containing 3 or 4 nitrogen heteroatoms which is linked to the quinoxalinedione ring by a ring carbon or nitrogen atom, or is a 6-membered ring heteroaryl group containing from 1 to 3 nitrogen heteroatoms which is linked to the quinoxalinedione ring by a ring carbon atom, either of said groups being optionally benzo-fused and optionally substituted, including in the benzo-fused portion, by 1 or 2 substituents each independently selected from C1-C4 alkyl, C2-C4 alkenyl, C3-C7 cycloalkyl, halo, hydroxy, C1-C4 alkoxy, C3-C7 cycloalkyloxy, xe2x80x94COOH, C1-C4 alkoxycarbonyl, xe2x80x94CONR3R4, xe2x80x94NR3R4, xe2x80x94S(O)p(C1-C4 alkyl), xe2x80x94SO2NR3R4, aryl, aryloxy, aryl(C1-C4)alkoxy and het, said C1-C4 alkyl being optionally substituted by C3-C7 cycloalkyl, halo, hydroxy, C1-C4 alkoxy, halo(C1-C4)alkoxy, C3-C7 cycloalkyloxy, C3-C7 cycloalkyl(C1-C4)alkoxy, xe2x80x94COOH, C1-C4 alkoxycarbonyl, xe2x80x94CONR3R4, xe2x80x94NR3R4, xe2x80x94S(O)p(C1-C4 alkyl), xe2x80x94SO2(aryl), xe2x80x94SO2NR3R4, morpholino, aryl, aryloxy, aryl(C1-C4)alkoxy or het, and said C2-C4 alkenyl being optionally substituted by aryl;
R1 and R2 are each independently selected from H, fluoro, chloro, bromo, C1-C4 alkyl and halo(C1-C4)alkyl;
R3 and R4 are either each independently selected from H and C1-C4 alkyl or, when taken together, are C5-C7 alkylene;
p is 0, 1 or 2;
xe2x80x9carylxe2x80x9d, used in the definition of R and xe2x80x9chetxe2x80x9d, means phenyl or naphthyl, each optionally substituted by 1 or 2 substitutents each independently selected from C1-C4 alkyl, C1-C4 alkoxy, hydroxy, halo, halo(C1-C4)alkyl and xe2x80x94NR3R4;
xe2x80x9chetxe2x80x9d, used in the definition of R, means furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl, each being optionally benzo-fused and optionally substituted, including in the benzo-fused portion, by 1 or 2 substituents each independently selected from C1-C4 alkyl, C3-C7 cycloalkyl, C1-C4 alkoxy, halo, hydroxy, xe2x80x94COOH, C1-C4 alkoxycarbonyl, allyloxycarbonyl, xe2x80x94CONR3R4, xe2x80x94NR3R4, xe2x80x94S(O)p(C1-C4 alkyl), xe2x80x94SO2NR3R4, halo(C1-C4)alkyl, hydroxy(C1-C4)alkyl, C1-C4 alkoxy(C1-C4)alkyl, R3R4NCO(C1-C4)alkyl, aryl, arylalkyl, het1 and het1(C1-C4)alkyl, and/or by an oxido substituent on a ring nitrogen heteroatom when xe2x80x9chetxe2x80x9d includes a pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl group; and xe2x80x9chet1xe2x80x9d, used in the definition of xe2x80x9chetxe2x80x9d, means furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl. oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl, each optionally substituted by 1 or 2 C1-C4 alkyl substituents.
In the above definitions, xe2x80x9chaloxe2x80x9d means fluoro, chloro, bromo or iodo and alkyl, alkoxy and alkylene groups having three or more carbon atoms and alkenyl groups having 4 or more carbon atoms can be straight- or branched-chain.
The definition xe2x80x9cC1-C4 alkylxe2x80x9d covers methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl and tert-butyl groups. The definition xe2x80x9cC1-C4 alkoxyxe2x80x9d covers the corresponding alkoxy groups.
Where R is a 5-membered ring heteroaryl group, this definition covers 1,2,3-triazolyl, 1,2,4-triazolyl and tetrazolyl.
Where R is a 6-membered ring heteroaryl group, this definition includes, in particular, 2-, 3- and 4-pyridinyl, 3- or 4pyridazinyl, 2-, 4- or 5-pyrimidinyl and 2-pyrazinyl.
Where xe2x80x9chetxe2x80x9d is a benzo-fused heteroaryl group, this may be attached to the remainder of the molecule via the heteroaryl or benzo-fused portion of the xe2x80x9chetxe2x80x9d group.
Preferably, R is triazolyl or tetrazolyl, each substituted by 1 or 2 substituents each independently selected from C1-C4 alkyl, C2-C4 alkenyl, C3-C7 cycloalkyl, halo, hydroxy, C1-C4 alkoxycarbonyl, aryl and het, said C1-C4 alkyl being optionally substituted by halo, hydroxy, C1-C4 alkoxy, halo(C1-C4)alkoxy, C3-C7 cycloalkyl(C1-C4)alkoxy, xe2x80x94COOH, C1-C4 alkoxycarbonyl, xe2x80x94NR3R4, xe2x80x94SO2(aryl), morpholino, aryl, aryloxy, aryl(C1-C4)alkoxy or het; or is pyridinyl or pyrimidinyl.
More preferably, R is 1,2,3-triazol-4-yl, 1,2,4-triazol-3yl, 1,2,4-triazol-4-yl or tetrazol-5yl, each substituted by 1 or 2 substituents each independently selected from C1-C4 alkyl, C2-C4 alkenyl, C3-C7 cycloalkyl, halo, hydroxy, C1-C4 alkoxycarbonyl, aryl and het, said C1-C4 alkyl being optionally substituted by halo, hydroxy, C1-C4 alkoxy, halo(C1-C4)alkoxy, C3-C7 cycloalkyl(C1-C4)alkoxy. xe2x80x94COOH, C1-C4 alkoxycarbonyl, xe2x80x94NR3R4, xe2x80x94SO2(aryl), morpholino, aryl, aryloxy, aryl(C1-C4)alkoxy or het; or is pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl or pyrimidin-5-yl. Yet more preferably, R is 1,2,3-triazol-4yl, 1,2,4-triazol-3yl, 1,2,4-triazol-4-yl or tetrazol-5-yl, each substituted by 1 or 2 substituents each independently selected from methyl, ethyl, propyl, allyl, cyclopropyl, cyclohexyl, bromo, hydroxy, ethoxycarbonyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 4-dimethylaminophenyl, 2-hydroxyphenyl, 2-methoxyphenyl, 3-methoxyphenyl, -4-methoxyphenyl, 2-methylphenyl, phenyl, 4-trifluoromethylphenyl, 2-amino-1,3,4-oxadiazol-5-yl, 2-carboxypyridin-5-yl, 1.5-dimethyl-1H-pyrazol-3-yl, 1H-imidazol-1-yl, 1-methylimidazol-2-yl, 1-methylimidazol-4-yl, 1-methylimidazol-5-yl, 3-methylisothiazol-4-yl, 4-methyl-1H-imidazol-5-yl, 3-methyl-1,2,4-oxadiazol-5-yl, 1-methyl-1H-pyrazol-4yl, 5-methyl-1H-pyrazol-3-yl, 1-methyl-1H-pyrazol-5-yl, 1-oxidopyridin-3-yl, 2-methylpyridin-3-yl, 2-methypyridin-5-yl, 1-phenylimidazol-4-yl, 5-phenylpyridin-3-yl, 2-phenylpyridin-5-yl, 1-methylpyrrol-2-yl, 4-methyl-1,2,3-thiadiazol-5yl, 2-methylthiazol-4-yl, 1-methyl-1H-1,2,4-triazol-5-yl, 3-(prop-1-yl)-1H-pyrazol-5-yl, pyrazin-2-yl, 1H-pyrazol-4-yl, pyridazin-4-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl, thien-2-yl, 1H-1,2,4-triazol-5yl, 1H-1,2,3-triazol-5-yl, quinolin-3-yl and quinolin-6-yl, said methyl, ethyl or propyl being optionally substituted by fluoro, hydroxy, methoxy, ethoxy, 2,2,2-trifluoroethoxy, cyclohexylmethoxy, cyclopentylmethoxy, xe2x80x94COOH, methoxycarbonyl, dimethylamino, 4-chlorophenylsulphonyl, morpholino, phenyl, phenoxy, benzyloxy, pyridin-2-yl, pyridin-3-yl or pyridin-4-yl; or is pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl or pyrimidin-5-yl.
Examples of R include:
1-(2-hydroxyethyl)-5-phenyl-1,2,3-triazol-4-yl,
1-(2-hydroxyethyl)-4-phenyl-1,2,3-triazol-5-yl,
2-(2-hydroxyethyl)-5-phenyl-1,2,3-triazol-4-yl,
1-methyl-5-phenyl-1,2,3-triazol-4-yl,
1-methyl-4-phenyl-1,2,3-triazol-5-yl,
2-methyl-5phenyl-1,2,3-triazol-4-yl,
5-phenyl-1H-1,2,3-triazol-4-yl.
1-methyl-1H-1,2,4-triazol-3-yl,
2-methyl-2H-1,2,4-triazol-3-yl,
4-(2-hydroxyethyl)-4H-1,2,4-triazol-3-yl,
4-methyl-4H-1,2,4-triazol-3-yl,
3(2-amino-1,3,4-oxadiazol-5-yl)-5-methyl-4H-1,2,4-triazol-4-yl,
3-benzyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-4-yl,
3-benzyloxymethyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-4-yl,
3-bromo-5-(pyridin-3-yl)-4H-1,2,4-triazol-4-yl,
3-(3-carboxyprop-1-yl)-5-(pyridin-3-yl)-4H-1,2,4-triazol-4-yl,
3-(2-carboxypyridin-5-yl)-5-methoxymethyl-4H-1,2,4-triazol-4-yl,
3-(2-chlorophenyl)-5-methoxymethyl-4H-1,2,4-triazol-4-yl,
3-(2-chlorophenyl)-5-methyl-4H-1,2,4-triazol-4-yl,
3-(3-chlorophenyl)-5-methyl-4H-1,2,4-triazol-4-yl,
3-(4-chlorophenyl)-5-methyl-4H-1,2,4-triazol-4-yl,
3-(4-chlorophenylsulphonylmethyl)-5-methyl-4H-1,2,4-triazol-4-yl,
3-cyclohexylmethoxymethyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-4-yl,
3-cyclopentylmethoxymethyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-4-yl,
3-cyclopropyl-5-methyl-4H-1,2,4-triazol-4yl,
3,5-di(methoxymethyl)-4H-1,2,4-triazol-4-yl,
3-(N,N-dimethylaminomethyl)-5-ethyl-4H-1,2,4-triazol-4-yl,
3-(N,N-dimethylaminomethyl)-5_(pyridin-3-yl)-4H-1,2,4-triazol-4-yl,
3-(4-dimethylaminophenyl)-5methyl-4H-1,2,4-triazol-4-yl,
3-(1,5-dimethyl-1H-pyrazol-3-yl)-5-methoxymethyl-4H-1,2,4-triazol-4yl,
3-(1,5-dimethyl-1H-pyrazol-3-yl)-5-methyl-4H-1,2,4-triazol-4-yl,
3,5-dimethyl-4H-1,2,4-triazol-4-yl,
3,5-diphenyl-4H-1,2,4-triazol-4-yl,
3-(2-ethoxyethyl)-5-(pyridin-3-yl)-4H-1,2,4-triazol-4-yl,
3-ethoxymethyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-4-yl,
3-ethoxycarbonyl-4H-1,2,4-triazol-4-yl,
3-ethyl-5-(2-chlorophenyl)-4H-1,2,4-triazol-4-yl,
3-ethyl-5-(2-methoxyphenyl)-4H-1,2,4-triazol-4-yl,
3-ethyl-5-(1-methylpyrazol-5-yl)-4H-1,2,4-triazol-4-yl,
3-ethyl-5-methyl-4H-1,2,4-triazol-4-yl,
3-ethyl-5-morpholinomethyl-4H-1,2,4-triazol-4-yl,
3-ethyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-4-yl,
3-ethyl-4H-1,2,4-triazol-4-yl,
3-(2-hydroxyethyl)-5-methyl-4H-1,2,4-triazol-4-yl,
3-hydroxymethyl-5-methyl-4H-1,2,4-triazol-4-yl,
3-hydroxymethyl-5-phenyl-4H-1,2,4-triazol-4-yl,
3-hydroxymethyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-4-yl,
3-hydroxymethyl-4H-1,2,4-triazol-4-yl,
3-hydroxy-5-methyl-4H-1,2,4-triazol-4-yl,
3-(2-hydroxyphenyl)-5-methyl-4H-1,2,4-triazol-4-yl,
3-(1H-imidazol-1-yl)-5-methyl-4H-1,2,4-triazol-4yl,
3-(2-methoxyethyl)-5-(pyridin-3-yl)-4H-1,2,4-triazol-4yl,
3-methoxymethyl-5-(1-methyl-1H-pyrazol-5-yl)-4H-1,2,4-triazol-4-yl,
3-methoxymethyl-5-(1-methylpyridin-5-yl)-4H-1,2,4-triazol-4-yl,
3-methoxymethyl-5-(2-methylthiazol-4yl)-4H-1,2,4-triazol-4-yl,
3-methoxymethyl-5-(1-oxidopyridin-3-yl)-4H-1,2,4-triazol-4-yl,
3-methoxymethyl-5-(1-phenylimidazol-4-yl)-4H-1,2,4-triazol-4-yl,
3-methoxymethyl-5-(5-phenylpyridin-3-yl)-4H-1,2,4-triazol-4-yl,
3-methoxymethyl-5-(2-phenylpyridin-5-yl)-4H-1,2,4-triazol-4-yl,
3-methoxymethyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-4-yl,
3-methoxymethyl-5-(pyridin-3-ylmethyl)-4-H1,2,4-triazol-4-yl,
3-methoxymethyl-5-(quinolin-3-yl)-4H-1,2,4-triazol-4-yl,
3-methoxymethyl-5-(quinolin-6-yl)-4H-1,2,4-triazol-4-yl,
3-(2-methoxyphenyl)-5-methyl-4H-1,2,4-triazol-4-yl,
3-(3-methoxyphenyl)-5-methyl-4H-1,2,4-triazol-4-yl,
3-(4-methoxyphenyl)-5-methyl-4H-1,2,4-triazol-4-yl
3-methyl-5-(1-methylimidazol-2-yl)-4H-1,2,4-triazol-4-yl,
3-methyl-5-(1-methylimidazol-4-yl)-4H-1,2,4-triazol-4-yl,
3-methyl-5-(1-methylimidazol-5-yl)-4H-1,2,4-triazol-4-yl,
3-(3-methylisothiazol-4-yl)-5-methyl-4H-1,2,4-triazol-4-yl,
3-methyl-5-(4-methyl-1H-imidazol-5-yl)-4H-1,2,4-triazol-4-yl,
3-methyl-5-(3-methyl-1,2,4-oxadiazol-5-yl)-4H-1,2,4-triazol-4-yl,
3-methyl-5-(2-methylpyridin-3-yl)-4H-1,2,4-triazol-4-yl,
3-methyl-5-(2-methylpyridin-5-yl)-4H-1,2,4-triazol-4-yl,
3-methyl-5-(1-methylpyrazol-5-yl)-4H-1,2,4-triazol-4-yl,
3-methyl-5-(5-methyl-1H-pyrazol-3-yl)-4H-1,2,4-triazol-4-yl,
3-methyl-5-(2-methylphenyl)-4H-1,2,4-triazol-4-yl,
3-methyl-5-(1-methylpyrrol-2-yl)-4H-1,2,4-triazol-4-yl,
3-methyl-5-(4-methyl-1,2,3-thiadiazol-5yl)-4H-1,2,4-triazol-4-yl,
3-methyl-5-(2-methylthiazol-4-yl)-4H-1,2,4-triazol-4-yl,
3-methyl-5-(1-methyl-1H-1,2,4-triazol-5-yl)-4H-1,2,4-triazol-4-yl,
3-methyl-5-(1-methyl-1H-pyrazol-4-yl)-4H-1,2,4-triazol-4-yl,
3-(3-methyl-1,2,4-oxadiazol-5-yl)-5-(pyridin-3-yl)-4H-1,2,4-triazol-4-yl,
3-methyl-5-phenyl-4H-1,2,4-triazol-4yl,
3-methyl-5-(3-[prop-1-yl]-1H-pyrazol-5-yl)-4H-1,2,4-triazol-4-yl,
3-methyl-5-(pyrazin-2-yl)-4H-1,2,4-triazol-4-yl,
3-methyl-5-(1H-pyrazol-4-yl)-4H1,2,4-triazol-4-yl,
3-methyl-5-(pyridin-2-yl)-4H-1,2,4-triazol-4-yl,
3-methyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-4-yl,
3-methyl-5-(pyridin-4-yl)-4H-1,2,4-triazol-4-yl,
3-methyl-5-(pyridin-2-ylmethyl)-4H-1,2,4-triazol-4-yl,
3-methyl-5-(pyridin-3-ylmethyl)-4H-1,2,4-triazol-4-yl,
3-methyl-5-(pyridin-4-ylmethyl)-4H-1,2,4-triazol-4-yl,
3-methyl-5-(pyridazin-4-yl)-4H-1,2,4-triazol-4-yl,
3-methyl-5-(pyrimidin-2-yl)-4H-1,2,4-triazol-4-yl,
3-methyl-5-(thien-2-yl)-4H-1,2,4-triazol-4-yl,
3-methyl-4H-1,2,4-triazol-4-yl,
3-methyl-5-(1H-1,2,3-triazol-5-yl)-4H-1,2,4-triazol-4-yl,
3-methyl-5-(1H-1,2,4-triazol-5-yl)-4H-1,2,4-triazol-4-yl,
3-morpholinomethyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-4-yl,
3-phenoxymethyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-4-yl,
3-(2-phenylethyl)-5-(pyridin-3-yl)-4H-1,2,4-triazol-4-triazol-4-yl,
3-(pyridin-3-yl)-4H-1,2,4-triazol-4-yl,
3-methyl-5-(4-trifluoromethylphenyl)-4H-1,2,4-triazol-4-yl,
1-allytetrazol-5-yl,
1-benzyltetrazol-5-yl,
1-carboxymethyltetrazol-5-yl,
1-cyclohexyltetrazol-5-yl,
1-ethyltetrazol-5-yl,
1-(2-hydroxyethyl)tetrazol-5-yl,
1-(3-hydroxypropyl)tetrazol-5-yl,
1-methoxycarbonylmethyltetrazol-5-yl,
1-(2-methoxyethyl)tetrazol-5yl,
1-methyltetrazol-5-yl,
1-(2-phenylethyl)tetrazol-5-yl,
1-phenyltetrazol-5-yl,
1-(prop-2-yl)tetrazol-5-yl,
1-(2,2,2-trifluoroethyl)tetrazol-5-yl,
pyridin-2-yl,
pyridin-3-yl,
pyridin-4-yl,
pyrimidin-2-yl and
pyrimidin-5-yl.
Most preferably R is
1-(3-hydroxypropyl)tetrazol-5-yl,
4-methyl-4H-1,2,4-triazol-3-yl,
1-(2-hydroxyethyl)-5-phenyl-1,2,3-triazol-4-yl,
3-methyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-4-yl,
3-methyl-5-(pyridin-3-ylmethyl)-4H-1,2,4-triazol-4-yl,
3-methoxymethyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-4-yl,
3-methoxymethyl-5-(quinolin-3-yl)-4H-1,2,4-triazol-4-yl,
3-methoxymethyl-5-(quinolin-6-yl)-4H-1,2,4-triazol-4-yl
or 3-(1,5-dimethyl-1H-pyrazol-3-yl)-5-methyl-4H-1,2,4-triazol-4-yl.
Preferably, R1 and R2 are each independently selected from chloro and C1-C4 alkyl, especially methyl or ethyl. Most preferably, R1 and R2 are each chloro.
Preferably, R3 and R4 are each independently selected from H and C1-C4 alkyl. Most preferably, R3 and R4 are each methyl.
Preferably, xe2x80x9carylxe2x80x9d means phenyl optionally substituted by 1 or 2 substituents each independently selected from methyl, methoxy, hydroxy, chloro, trifluoromethyl and dimethylamino. Examples of xe2x80x9carylxe2x80x9d include 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 4-dimethylaminophenyl, 2-hydroxyphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-methylphenyl, phenyl and 4-trifluoromethylphenyl.
Preferably, xe2x80x9chetxe2x80x9d means thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl, each being optionally benzo-fused and optionally substituted by 1 or 2 substituents each independently selected from C1-C4 alkyl, xe2x80x94COOH, xe2x80x94NR3R4 and phenyl, and/or by an oxido substituent on a ring nitrogen heteroatom of said pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl group.
Examples of xe2x80x9chetxe2x80x9d include thien-2yl, 1-methylpyrrol-2yl, 1H-pyrazol-4-yl, 1-methyl-1H-pyrazol-4-yl, 5-methyl-1H-pyrazol-3-yl, 1-methyl-1H-pyrazol-4-yl, 1,5-dimethyl-1H-pyrazol-3-yl, 3-(prop-1-yl)-1H-pyrazol-5-yl, 1H-imidazol-1-yl, 1-methylimidazol-2-yl, 1-methylimidazol-4yl, 1-methylimidazol-5-yl, 4-methyl-1H-imidazol-5-yl, 1-phenylimidazol-4-yl, 1H-1,2,3-triazol-5-yl, 1H-1,2,4-triazol-5-yl, 1-methyl-1H-1,2,4-triazol-5-yl, 2-methylthiazol-4-yl, 3-methylisothiazol-4-yl, 2-amino-1,3,4-oxadiazol-5-yl, 3-methyl-1,2,4-oxadiazol-5-yl, 4-methyl-1,2,3-thiadiazol-5-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2-methylpyridin-3-yl, 2-methylpyridin-5-yl, 1-oxidopyridin-3-yl, 2-carboxypyridin-5-yl, 5-phenylpyridin-3-yl, 2-phenylpyridin-5-yl, pyridazin-4yl, pyrimidin-2-yl, pyrazin-2-yl, quinolin-3yl and quinolin-6-yl.
The pharmaceutically acceptable salts of the compounds of the formula (I) include the acid addition and the base salts thereof.
Suitable acid addition salts are formed from acids which form non-toxic salts and examples are the hydrochloride, hydrobromide, hydroiodide, sulphate, hydrogen sulphate, nitrate, phosphate, hydrogen phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, succinate, benzoate, methanesulphonate, benzenesulphonate and p-toluenesulphonate salts.
Suitable base salts are formed from bases which form non-toxic salts and examples are the calcium, lithium, magnesium, potassium, sodium, zinc, ethanolamine, diethanolamine and triethanolamine salts.
For a review on suitable salts see Berge et al, J. Pharm. Sci., 66, 1-19 (1977).
A compound of the formula (I) may contain one or more asymmetric carbon atoms and may therefore exist in two or more stereoisomeric forms, or it may exist as tautomers. The present invention includes the individual stereoisomers and tautomers of the compounds of the formula (I) and mixtures thereof.
Separation of diastereoisomers may be achieved by conventional techniques, e.g. by fractional crystallisation, chromatography or H.P.L.C. of a stereoisomeric mixture of a compound of the formula (I) or a suitable salt or derivative thereof. An individual enantiomer of a compound of the formula (I) may also be prepared from a corresponding optically pure intermediate or by resolution, such as by H.P.L.C. of the corresponding racemate using a suitable chiral support or by fractional crystallisation of the diastereoisomeric salts formed by reaction of the corresponding racemate with a suitable optically active acid or base.
Certain compounds of the formula (I) can exist in the form of particular stereoisomers known as atropisomers. Atropisomers are isomers that can be separated only because rotation about single bonds is prevented or greatly slowed (see xe2x80x9cAdvanced Organic Chemistryxe2x80x9d, Third Edition, Jerry March, John Wiley and Sons (1985)). They can be separated by conventional methods such as by those described in the preceding paragraph. The present invention includes the individual atropisomers of the compounds of the formula (I) and mixtures thereof.
Preferred examples of the compounds of the formula (I) are those wherein
(i) R is 1-(3-hydroxypropyl)tetrazol-5-yl, R1 is chloro and R2 is chloro;
(ii) R is 4-methyl-4H-1,2,4-triazol-3-yl, R1 is chloro and R2 is chloro;
(iii) R is 1-(2-hydroxyethyl)-5-phenyl-1,2,3-triazol-4-yl, R1 is chloro and R2 is chloro;
(iv) R is 3-methyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-4-yl, R1 is chloro and R2 is chloro;
(v) R is 3-methyl-5-(pyridin-3-ylmethyl)-4H-1,2,4-triazol-4-yl, R1 is chloro and R2 is chloro;
(vi) R is 3-methoxymethyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-4-yl, R1 is chloro and R2 is chloro;
(vii) R is 3-(1,5-dimethyl-1H-pyrazol-3-yl)-5-methyl-4H-1,2,4-triazol-4-yl, R1 is chloro and R2 is chloro;
(viii) R is 3-methoxymethyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-4-yl, R1 is chloro and R2 is methyl;
(ix) R is 3-methoxymethyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-4-yl, R1 is methyl and R2 is chloro;
(x) R is 3-methoxymethyl-5-(quinolin-3-yl)-4H-1,2,4-triazol-4-yl, R1 is chloro and R2 is chloro; or
(xi) R is 3-methoxymethyl-5-(quinolin-6-yl)-4H-1,2,4-triazol-4-yl, R1 is chloro and R2 is chloro: or an individual stereoisomer or a pharmaceutically acceptable salt of any thereof. Particularly preferred compounds of the formula (I) are
(i) R-(-)-6,7-dichloro-5-[3-methoxymethyl-5-(3-pyridyl)-4H-1,2,4-triazol-4-yl]-2,3(1H,4H)-quinoxalinedione or a pharmaceutically acceptable salt there of and
(ii) R-(-)-6,7-dichloro-5-[3-methoxymethyl-5-(3-pyridyl)-4H-1,2,4-triazol-4-yl]-2,3(1H,4H)-quinoxalinedione sodium salt.
All the compounds of the formula (I) can be prepared by acidic or basic hydrolysis of a compound of the formula: 
wherein R, R1 and R2 are as previously defined for a compound of the formula (I) and R5 and R6, either when taken alone or together, represent a group or groups that can be hydrolytically cleaved under acidic or basic conditions to provide a quinoxalinedione of the formula (I). Such group or groups are conventional and suitable examples will be well-known to the skilled person.
Preferably R5 and R6 are either each independently selected from C1-C4 alkyl (preferably methyl or ethyl) and benzyl, optionally ring-substituted by from 1 to 3 substituents each independently selected from C1-C4 alkyl, C1-C4 alkoxy, halo, nitro and trifluoromethyl, or, when taken together, represent C1-C5 alkylene, CH(phenyl), CH(4-methoxyphenyl) or CH(3,4-dimethoxyphenyl).
Preferably, the reaction is carried out by acidic hydrolysis of a compound of the formula (II).
In a typical procedure, a compound of the formula (II) is treated with an aqueous solution of a suitable acid, e.g. a mineral acid such as hydrochloric acid, optionally in the presence of a suitable organic co-solvent, e.g. 1,4-dioxane. The reaction is usually carried out by heating the mixture at up to the reflux temperature of the solvent(s). The intermediates of the formula (II) can be prepared by a variety of conventional methods, for example, as described below.
(a) The compounds of the formula (II) where R is a substituted tetrazol-5-yl group can be prepared by the route shown in Scheme I: 
wherein R1, R2, R5 and R6 are as previously defined for a compound of the formula (II) and Rc is a suitable substituent as previously defined for R for a compound of the formula (I). In a typical procedure, a compound of the formula (III) is first deprotonated with a suitable base, e.g. lithium diisopropylamide, in a suitable solvent, e.g. tetrahydrofuran, and the carbanion obtained is then treated with carbon dioxide. The carboxylic acid of the formula (IV) obtained is converted to the corresponding acid chloride using oxalyl chloride and a catalytic amount of N,N-dimethylformamide in a suitable solvent, e.g. dichloromethane, which is then converted to the secondary amide of the formula (V) by in situ treatment with an amine of the formula:
RCNH2. 
The amide of the formula (V) is first treated with phosphorus pentachloride in a suitable solvent, e.g. toluene, and the intermediate obtained is reacted in situ with trimethylsilyl azide to provide a compound of the formula (IIA).
(b) The compounds of the formula (II) where R is an optionally benzo-fused/substituted 5-or 6-membered ring heteroaryl group which is linked to the quinoxaline ring by a ring carbon atom, can be prepared by the route shown in Scheme II: 
wherein R1, R2, R5 and R6 are as previously defined for a compound of the formula (II) and RD is an optionally benzo-fused/substituted 5- or 6-membered ring heteroaryl group which is linked to the quinoxaline ring by a ring carbon atom as previously defined for R for a compound of the formula (I). In a typical procedure, a compound of the formula (III) is first deprotonated as described in method (a) above and then treated in situ with trimethyl borate, followed by acid hydrolysis in the work-up, to provide a boronic acid of the formula (VI). This is then reacted with a compound of the formula:
RDX 
wherein X is bromo, iodo, or trifluoromethylsulphonyloxy, and RD is as defined above, in the presence of a suitable catalyst, e.g. tetrakis(triphenylphosphine)palladium (O), and under suitable conditions to provide a compound of the formula (IIB).
(c) The compounds of the formula (II) where R is an optionally 4-substituted-4H-1,2,4-triazol-3-yl group can be prepared by treatment of a compound of the formula (V) first with phosphorus pentachloride in a suitable solvent, e.g. toluene, followed by reaction of the intermediate obtained in situ with formyl hydrazine in the presence of a suitable base, e.g. triethylamine.
(d) The compounds of the formula (II) where R is a 1- or 2-(optionally substituted C1-C4 alkyl)-substituted-1,2,4-triazol-3-yl group can be prepared by treatment of a compound of the formula (V) where RC is H with a N,N-di(C1-C4 alkyl)formamide di(C1-C4 alkyl)acetal, preferably N,N-dimethylformamide dimethyl acetal, reacting the intermediate formamidine obtained with hydrazine in the presence of a suitable acid, e.g. acetic acid, and then by treatment of the resulting tautomeric mixture of 5-(1H-and 2H-1,2,4-triazol-3-yl)-substituted quinoxalines first with a suitable base, e.g. sodium hydride, in a suitable solvent, e.g. N,N-dimethylformamide, followed by a suitable optionally substituted C1-C4 alkyl halide (e.g. iodomethane to prepare N-methyl-substituted products). The mixture of 1- and 2-(optionally substituted C1-C4 alkyl)-substituted-1,2,4-triazol-3-yl products obtained can be separated by a conventional method e.g. chromatography.
(e) The compounds of the formula (II) where R is an optionally substituted 1,2,4-triazol-4-yl group can be prepared by the route shown in Scheme III: 
wherein R1, R2, R5 and R6 are as previously defined for a compound of the formula (II) and RA and RB are each independently H or a suitable substituent as previously defined for R for a compound of the formula (I). In a typical procedure, a 5-aminoquinoxaline of the formula (VII) is reacted with a compound of the formula:
RACOX1 
wherein X1 is a suitable leaving group, e.g. chloro or bromo, in a suitable solvent, e.g. toulene or dichloromethane, and optionally in the presence of a suitable acid acceptor, e.g. pyridine, to provide an amide of the formula (VIII). An amide of the formula (VIII) can be converted to a thioamide of the formula (IX) by treatment with 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulphide (Lawesson""s reagent) in a suitable solvent, e.g. toulene or tetrahydrofuran. A thioamide of the formula (IX) can be converted to a compound of the formula (IIC) by treatment with a compound of the formula:
RBCONHNH2
in the presence of mercury (II) oxide, optionally a desiccant, e.g. 4A molecular sieves, and a suitable solvent, e.g. n-butanol.
(f) The compounds of the formula (II) where R is an optionally benzo-fused/substituted 5- or 6-membered ring heteroaryl group which is linked to the quinoxaline ring by a ring carbon atom can be prepared by coupling a compound of the formula: 
where R1, R2, R5 and R6 are as previously defined for a compound of the formula (II), with a compound of the formula:
REX2
where X2 is Sn(C1-C4 alkyl)3, ZnCl, ZnBr, Znl or xe2x80x94B(OH)2, and RE is as defined for this method for R, in the presence of a suitable catalyst, e.g. tetrakis(triphenylphosphine)palladium (O), under suitable conditions.
(g) The compounds of the formula (II) where R is an optionally substituted 1,2,3-triazol-4-yl group can be prepared by the route shown in Scheme IV: 
wherein R1, R2, R5 and R6 are as previously defined for a compound of the formula (II) and RF is H, or RF and RG are each independently a suitable substituent as previously defined for R for a compound of the formula (I). In a typical procedure, a 5-iodoquinoxaline of the formula (X) is coupled with an acetylene of the formula:
RFxe2x80x94Cxe2x89xa1CH 
under suitable conditions, e.g. using bis(triphenylphosphine)palladium (II) chloride, copper (I) iodide and triethylamine. The compound of the formula (XI) prepared is then reacted with trimethylsilyl azide to provide a compound of the formula (IID) which can be converted to a compound of the formula (IIE) by a conventional method, e.g. where RG is C1-C4 alkyl, by first deprotonating a compound of the formula (IID) using a suitable base, e.g. sodium hydride, followed by reaction with a C1-C4 alkyl halide, e.g. iodomethane. Where a mixture of the 1-, 2- and 3-substituted-1,2,3-triazol-4-yl isomers of a compound of the formula (IIE) is obtained, these may be separated by a conventional method, e.g. chromatography.
It will be realised that certain compounds of the formula (I) or (II) may be converted to other compounds of the formula (I) or (II), respectively, by conventional methods, e.g. by functional group interconversion techniques.
All of the above reactions and the preparations of novel starting materials used in the preceding methods are conventional and appropriate reagents and reaction conditions for their performance or preparation as well as procedures for isolating the desired products will be well known to those skilled in the art with reference to literature precedents and the Examples and Preparations hereto.
A pharmaceutically acceptable acid addition or base salt of a compound of the formula (I) may be readily prepared by mixing together solutions of a compound of the formula (I) and the desired acid or base, as appropriate. The salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent.
The binding affinity of the compounds of the formula (I) and their salts for the glycine site of the NMDA receptor may be measured by testing their ability to displace a selective glycine site radioligand from rat brain membranes as described in Brit. J. Pharm., 104, 74 (1991). In a variation of this method, thoroughly washed membrane protein is incubated with [3H]-L-689,560 (Mol.Pharmacol., 41, 923 (1992)) for 90 minutes using tris-acetate buffer (pH 7.4). Displacement of the radioligand, using a range of test compound concentrations, is used to derive IC50 (50% inhibitory concentration) values.
Functional in vitro glycine antagonism is demonstrated by the ability of the compounds to inhibit the depolarizations in rat cortical slices induced by NMDA by a similar method to that described in J. Med. Chem., 33, 789 (1990) and Brit. J. Pharm., 84, 381 (1985). In a variation of the procedure, the response to a standard concentration of NMDA is measured in the presence of a range of test compound concentrations and the results obtained are used to derive EC50 (50% effective concentration) values.
The binding affinity of the compounds of the invention for the AMPA receptor may be measured by testing their ability to displace for radioligand [3H]-AMPA from rat brain membranes. Membrane homogenate is incubated with radioligand (10 nM) in the presence or absence of test compounds at various concentrations at 4xc2x0 C. for 45 minutes. Free and bound radiolabel are separated by rapid filtration and radioactivity is measured by liquid scintillation counting.
The compounds of the formula (I) and their salts can be administered to a subject to be treated alone, but will generally be administered in admixture with a pharmaceutically acceptable diluent or carrier selected with regard to the intended route of administration and standard pharmaceutical practice. For example, they can be administered orally, including sublingually, in the form of tablets containing such excipients as starch or lactose, or in capsules or ovules either alone or in admixture with excipients, or in the form of elixirs, solutions or suspensions containing flavouring or colouring agents. They can be injected parenterally, for example, intravenously, intramuscularly or subcutaneously. For parenteral administration, they are best used in the form of a sterile aqueous solution which may contain other substances, for example, enough salts or glucose to make the solution isotonic with blood.
The compounds have potential for absorption through the gastrointestinal tract and thus administration by slow release formulations is also possible.
In general, a therapeutically effective daily oral dose of the compounds of formula (I) and their salts is likely to range from 0.1 to 100 mg/kg body weight of the subject to be treated, preferably 1 to 20 mg/kg, and an intravenous daily dose is likely to range from 0.01-20 mg/kg body weight of subject to be treated, preferably 0.1-20 mg/kg. The compounds of the formula (I) and their salts may also be administered by intravenous infusion at a dose which is likely to range from 0.01-10 mg/kg/hr.
Tablets or capsules of the compounds may be administered singly or two or more at a time, as appropriate.
The physician will determine the actual dosage which will be most suitable for an individual patient and it will vary with the age, weight and response of the particular patient. The above dosages are exemplary of the average case. There can, of course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention.
Alternatively, the compounds of the formula (I) can be administered by inhalation or in the form of a suppository or pessary, or they may be applied topically in the form of a lotion, solution, cream, ointment or dusting powder. An alternative means of transdermal administration is by use of a skin patch. For example, they can be incorporated into a cream consisting of an aqueous emulsion of polyethylene glycols or liquid paraffin. They can also be incorporated, at a concentration of between 1 and 10% by weight, into an ointment consisting of a white wax or white soft paraffin base together with such stabilisers and preservatives as may be required.
It is to be appreciated that reference to treatment includes prophylaxis as well as the alleviation of established symptoms of the disease.
Thus the invention further provides:
i) a pharmaceutical composition comprising a compound of the formula (I), or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable diluent or carrier;
ii) a compound of the formula (I), or a pharmaceutically acceptable salt or composition thereof, for use as a medicament;
iii) the use of a compound of the formula (I), or of a pharmaceutically acceptable salt or composition thereof, for the manufacture of a medicament for the treatment of a disease by producing an antagonist effect at a NMDA receptor;
iv) use as in (iii) where the disease is an acute neurodegenerative or a chronic neurological disorder;
v) a method of treatment of a mammal to treat a disease by producing an antagonist effect at a NMDA receptor, which comprises treating said mammal with an effective amount of a compound of the formula (I) or with a pharmaceutically acceptable salt or composition thereof;
vi) a method as in (v) where the disease is an acute neurodegenerative or a chronic neurological disorder; and
vii) a compound of the formula (II).
The following Examples and Preparations illustrate the preparation of the compounds of the formula (I) together with intermediates used in their synthesis.
Melting points were determined using a Buchi apparatus in glass capillary tubes and are uncorrected. Low Resolution Mass Spectroscopic (LRMS) data were recorded on a Fisons Trio 1000 Mass Spectrometer (thermospray using ammonium acetate in aqueous methanol as the carrier or atmospheric pressure chemical ionisation (APCI) using 97.5:2.5, by volume, methanol:acetic acid and gaseous nitrogen as the carrier). NMR data were recorded on a Bruker AC300 or a Varian Unity 300 NMR instrument (both 300 MHz) or a Unity Inova-400 (400 MHz) instrument and were consistent with the assigned structures. Flash chromatography was accomplished on Kieselgel 60 (230-400 mesh) from E. Merck, Darmstadt, Kieselgel 60 F254 plates from E. Merck were used for thin layer chromatography (TLC) and the compounds were visualized with UV light or chloroplatinic acid/potassium iodide solution. In cases where compounds analysed as hydrates, the presence of water was evident by the enhanced peak due to water in the proton NMR spectra. The purity of the compounds was carefully assessed using analytical TLC and proton NMR (300 MHz) and the latter technique was used to calculate the amount of solvent in solvated samples. In multistep sequences, the purity and structure of intermediates were verified spectroscopically by proton NMR. Proton NMR shifts are quoted in parts per million downfield from tetramethylsilane.
Some abbreviations familiar to those skilled in the art have been used in the Examples and Preparations.